The drug compound having the adopted name “Dasatinib” has a chemical name N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyridiminyl]amino]-5-thiazolecarboxamide, and is structurally represented by Formula I.

Dasatinib is sold under the trade name Sprycel®. Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblasticjeukemia (Ph+ ALL).
The PCT application WO2005077945 discloses several crystalline forms of Dasatinib which are designated as monohydrate, butanol solvate, ethanol solvate, crystalline neat form (N-6) and crystalline neat form (T1H1-7).
U.S. Pat. No. 7,973,045 discloses anhydrous form and various other solvates of Dasatinib. US '045 also disclose process for the preparation of amorphous dasatinib by evaporating the solvent from the suspension. The solvents used in the process were selected from dimethylformamide, 1,2-dichlorobenzene, propylene glycol, ethylene glycol and glycerol. Example 60 of US '045 discloses preparation of amorphous Dasatinib by slurring in propylene glycol and heating.
US20140343073A1 discloses process for the preparation of amorphous form of dasatinib by milling.
Dasatinib prepared by the methods known in the art contain related substances or impurities. These impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. One such impurity encountered in the Dasatinib Propylene Glycol solvate is the N-oxide impurity. The peroxide content in the Propylene Glycol solvent and environmental oxygen are the two sources for N-Oxide impurity formation during crystallization of Dasatinib.
The autoxidation and the exposure to atmospheric oxygen of certain organic solvents during storage result in the peroxide formation in such solvents. The uses of peroxide containing solvents for substances which are easily oxidized require the prior removal of accumulated peroxides. Also, peroxides concentration in the solvents can be minimized by using various techniques such as adsorption using activated carbon, alumina etc. or by chemical reduction such as use of antioxidants (Journal of Pharmaceutical Sciences, Volume 101, Issue 1, January 2012, Pages 127-139; Ind. Eng. Chem. Anal. Ed., 1946, 18 (1), pp 52-54).
Generally, impurities are identified spectroscopically and/or with another physical method, and then are associated with peak position, such as that in a chromatogram, or spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is measure in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time.”
Retention time can vary about a mean value based upon the condition of the instrumentation as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, those skilled in the art use the “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
The management of process related impurities is enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
It is desirable that there is a method for identifying, quantifying and separating the impurities formed as a result of the synthesis of Dasatinib.
An objective of the present invention is to provide a method for preparation of Dasatinib with high purity.
For a compound to be suitable for use as a therapeutic agent, the physical properties of the compound should be such that they do not negatively impact the effectiveness and cost of a formulated active ingredient.
The inventors of the present invention have surprisingly found a novel crystalline form of dasatinib and processes for their preparation.